18-9117869-T-C

Variant names:

• chr18-9117869-T-C
• rs906807
• NM_021074.5:c.86T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021074.5(NDUFV2):​c.86T>C​(p.Val29Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 1,595,082 control chromosomes in the GnomAD database, including 525,894 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47701 hom., cov: 32)
  • Exomes 𝑓: 0.81 (478193 hom.)
• Consequence: NDUFV2 NM_021074.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 1.58
• Publications: 54 publications found

Genes affected

NDUFV2 (HGNC:7717): (NADH:ubiquinone oxidoreductase core subunit V2) The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes the 24 kDa subunit of complex I, and is involved in electron transfer. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy. A non-transcribed pseudogene of this locus is found on chromosome 19. [provided by RefSeq, Oct 2009]

NDUFV2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000265257 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.578213E-7).
• BP6: Variant 18-9117869-T-C is Benign according to our data. Variant chr18-9117869-T-C is described in ClinVar as Benign. ClinVar VariationId is 9054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV2	NM_021074.5	c.86T>C	p.Val29Ala	missense_variant	Exon 2 of 8	ENST00000318388.11	NP_066552.2
NDUFV2	XR_243808.4	n.131T>C		non_coding_transcript_exon_variant	Exon 2 of 8
NDUFV2	XM_017025782.2	c.-2T>C		5_prime_UTR_variant	Exon 2 of 8		XP_016881271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV2	ENST00000318388.11	c.86T>C	p.Val29Ala	missense_variant	Exon 2 of 8	1	NM_021074.5	ENSP00000327268.6

Frequencies

GnomAD3 genomes AF: 0.790 AC: 120110 AN: 152030 Hom.: 47658 Cov.: 32

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.815

GnomAD2 exomes AF: 0.798 AC: 200495 AN: 251114 AF XY: 0.805

Gnomad AFR exome AF: 0.757

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 0.716

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.816

Gnomad OTH exome AF: 0.820

GnomAD4 exome AF: 0.813 AC: 1172718 AN: 1442934 Hom.: 478193 Cov.: 30 AF XY: 0.815 AC XY: 585798 AN XY: 719068

African (AFR) AF: 0.758 AC: 25118 AN: 33116

American (AMR) AF: 0.752 AC: 33600 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.896 AC: 23297 AN: 26006

East Asian (EAS) AF: 0.656 AC: 25902 AN: 39484

South Asian (SAS) AF: 0.862 AC: 73978 AN: 85786

European-Finnish (FIN) AF: 0.751 AC: 40075 AN: 53372

Middle Eastern (MID) AF: 0.884 AC: 5053 AN: 5716

European-Non Finnish (NFE) AF: 0.819 AC: 896805 AN: 1095090

Other (OTH) AF: 0.819 AC: 48890 AN: 59698

GnomAD4 genome AF: 0.790 AC: 120207 AN: 152148 Hom.: 47701 Cov.: 32 AF XY: 0.787 AC XY: 58539 AN XY: 74374

African (AFR) AF: 0.759 AC: 31465 AN: 41476

American (AMR) AF: 0.757 AC: 11583 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3097 AN: 3470

East Asian (EAS) AF: 0.713 AC: 3696 AN: 5186

South Asian (SAS) AF: 0.858 AC: 4144 AN: 4828

European-Finnish (FIN) AF: 0.745 AC: 7876 AN: 10568

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55648 AN: 68010

Other (OTH) AF: 0.812 AC: 1714 AN: 2112

Alfa AF: 0.814 Hom.: 22032

Bravo AF: 0.789

TwinsUK AF: 0.815 AC: 3021

ALSPAC AF: 0.831 AC: 3203

ESP6500AA AF: 0.761 AC: 3352

ESP6500EA AF: 0.819 AC: 7042

ExAC AF: 0.800 AC: 97097

Asia WGS AF: 0.720 AC: 2503 AN: 3478

EpiCase AF: 0.818

EpiControl AF: 0.824

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 7 Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jan 03, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Parkinson disease, mitochondrial Uncertain:1

Apr 01, 1998

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.2
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.026	T;T
MetaRNN	Benign	7.6e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.6	N;.
PhyloP100		1.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0	B;.
Vest4		0.070
MPC		0.040
ClinPred		0.0032	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.58
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs906807; hg19: chr18-9117867; COSMIC: COSV59186794; COSMIC: COSV59186794;